The development of appropriate pharmacological tools to allow the dissection of the pathological and physiological role of the kinin system in cardiovascular disease is the goal of this proposal. Proposed inhibitors of kallikrein based on the concepts of affinity labelling and transition state analogs will be synthesized as well as analogs of bradykinin which may compete for binding to the receptor. Analogs of bradykinin which are resistent to proteolytic attack and which retain their biological activity will also be developed as well as compounds which specifically inhibit the activity of the enzymes responsible for the degradation of bradykinin. These compounds will be tested and used in a number of systems in which kinins are thought to exert a major role. These include isolated and perfused tissues such as heart, lung and kidney where bradykinin is involved in a complex relationship with prostaglandins in the control of vasomotor tone. In intact animals, the role of bradykinin in myocardial ischemia and on the modification of baroreflexes will be ascertained. Finally the mechanism of action of bradykinin in inducing the synthesis of prostaglandins will be investigated.